Tunable polymeric composite coating for controlled release

ABSTRACT

A polymeric composite coating includes a drug release retardant polymer matrix, and pH-responsive nanoparticulate pore former. The pH-responsive pore formers function to modulate the permeability of the coating in response to pH changes which can compensate any changes in drug solubility with negligible leaching of the pore formers. The pH-responsive nanoparticulate pore formers may also function as alcohol-resistant component to the overall composite coating to resist increased solubility and permeability in presence of alcohol at 40% ethanol concentration in aqueous media. In one embodiment, the drug release retardant polymer is made of cellulose derivatives.

FIELD

The present disclosure relates generally to the field of controlledrelease of ingredients in pharmaceutical formulations, nutraceuticals,animal care products, and consumer products.

BACKGROUND

Controlled release of ingredients of interest in various products oftenutilizes a material such as a polymer membrane that form a barrier totransport of the ingredients from a formulation. The permeability of themembrane can be modified by adding a more permeable component to achievedesirable release kinetics. The permeability modifiers are generallycalled pore formers that change the porosity of the membrane.Hydrophilic, water-soluble polymers such as acrylic polymer, sodiumalginate, poly(vinyl pyrrolidone) (PVP), and hydroxypropyl methylcellulose (HPMC) have been applied as pore formers.

Although more prevalent in pharmaceuticals, uses of pore formers canalso be found in food and consumer products. Pore formers have been usedfor sustained release of vitamins and food supplements. A specificexamples include and folic acid being stored in ethyl cellulosemicrocapsules with sucrose as the pore former¹. Another application ofpore formers can be found in bags for holding contaminated waste forsteam sterilization and subsequent disposal². Carbowaxes of polyethyleneglycol was used as pore formers that dissolve and form pore in the bagto allow steam to enter and sterilize the contents².

While many efforts have been made, there remains a need for formulationsthat can provide pH-independent drug release without complex formulationdevelopment using several different excipients and/or parameters toadjust. Conventional pore formers such as HPMC, PVP, and polyacrylicacid quickly leach out of the controlled release formulations whenexposed to fluid, which would negatively impact the drug releasekinetics and mechanical strength of the membrane.

A major problem encountered by the use of conventional pore former, e.g.HPMC is the high viscosity of the coating suspension, leading to processchallenges. For example, addition of 10% HPMC to Surelease®(ethylcellulose) suspension increased the viscosity by over 5000 fold,which makes coating process difficult. Hence a nanoparticulate poreformer with little influence on the viscosity of coating suspension isapparently advantageous.

Ionizable drugs and their salts exhibit pH dependent solubility. Hence,controlled release matrices of these drugs show pH dependent releaserate in the gastrointestinal tract. In addition, gastric pH and gastricemptying are influenced by the presence of food, aging, diseases such asAIDS, and administration of acid suppressing agents such as antacids,H2-receptor antagonists (H2RAs), and proton-pump inhibitors (PPIs). ApH-dependent controlled release system could lead to inter-patient invivo variability and bioavailability problems. Hence, greater controlover release behavior of ionizable drugs and their salts assures a morereliable drug therapy³.

To overcome the problem of pH-dependent drug release two methods havebeen extensively studied by various research groups. One approach isbased on the addition of buffering agents to the core to maintain aconstant microenvironment pH and hence solubility, independent of thesurrounding pH. The second approach is based on the use of permeabilitymodifiers. The permeability modifiers are generally pore forming agentswhich are used to achieve a pH independent release of weakly basic drugsby leaching out and hence increasing the matrix permeability at higherpH values.

The incorporation of the pH modifiers are not as straight forward as onemight initially think. The ability to improve the release properties ofweakly basic and acidic drugs by adding organic buffers depends onseveral factors. These include the solubility of the buffers and thebuffering capacity together with the pK_(a) values and the solubility ofthe salts formed with the drug. The solubility of the buffers plays animportant role in maintaining a target pH value inside the dosage form.For example acids without adequate solubility, fumaric acid, only exertan effect for a limited duration⁴. Highly soluble acids such as tartaricand citric acids diffuse too rapidly with the drug through thefilm-coating. Often higher amounts of acids (up to 500% relative to thedrug) have to be used to achieve a pH-independent drug release over along period of time⁵. Akiyama et al showed that incorporation of highlysoluble pH modifiers are ineffective in controlling the pHmicroenvironment of microspheres of a weakly basic drug as theseexcipients diffused out of the matrix at a faster rate compared to thedrug itself. An insoluble pH modifier such as magnesium oxide proved tobe effective in achieving a pH-independent release profile as thisexcipient would stay in the matrix long enough to maintain its effect onpH. However, it has to be noted that a magnesium oxide to drug ratio ofat least 3 to 1 is required to achieve a pH-independent release⁶.

A pH-independent controlled release formulations of divalproex sodium, aweakly acidic drug, were developed using Eudragit® E100 or Fujicalin® asrelease modifiers. The formulations with Eudragit® E100 showed pHindependent release mainly due to increase in the pH microenvironment ofthe swollen gel layer. Fujicalin was less effective in achieving a pHindependent release. This was attributed to the relative inability toelevate the pH and shorter residence time of Fujicalin in the matrixrelative to Eudragit® E100⁷. Aditya et al. investigated the effect ofincorporating a polymeric pH modifier vs. an organic acid on the releasebehavior of trimethoprim (pK_(a)=6.6) matrix tablets⁸. Incorporation ofacrylic acid methacrylate co-polymer (Eudragit® L100-55) had marginaleffect on release behavior as the pH modulation effects were neutralizedby the basicity of the drug. In addition, water uptake and scanningelectron microscopy (SEM) studies suggested that Eudragit® L100-55incorporation also resulted in reduced water uptake and matrixpermeability. On the other hand, the reduction in the microenvironmentpH brought on by the incorporation of melanic acid was sufficiently highand persistence to result in pH-independent release⁷.

Another approach to develop pH-independent controlled release systemsfor weakly basic drugs is to incorporate ingredients which increase theporosity of the system, mostly by leaching out, to compensate for thereduction in the solubility. Incorporation of poly(methacrylic acid)into the papaverine microspheres, a basic drug, resulted inpH-independent release. SEM investigations revealed that the acrylicpolymer acted as a pore former at higher pH's and hence corrected forthe reduction in drug solubility by increasing the permeability of thematrix leading to a constant release rate. Kohri et al. developedpH-independent sustained release granules of dipyridamole which is aweakly basic drug⁹. The granules contained drug, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methyl cellulose (HPMC), and Eudragit®RS100, and exhibited pH independent release in pH 1.2-7. The authorsproposed that the drug release from such matrices below pH 4 should beimproved by dissolving HPMC and suppressed by CMEC and Eudragit® RS 100,while that above pH 5 should be enhanced by dissolving HPMC and CMEC andsuppressed by Eudragit RS 100. Comparison of this formulation with acommercial pH-dependent controlled release formulation in controlledgastric acidity rabbits revealed that the pH-independent granulesproduce drug plasma level concentrations with less degree of variabilitycompared to the conventional formulation⁹. A controlled release matrixcomposed of a weakly basic drug, a hydrophilic polymer (HPMC E-50) andan enteric polymer (Eudragit® L-100-SS) was developed by Oren andSeidler¹⁰. The enteric polymer is insoluble at low pH and acts as a partof the matrix retarding the drug release. At higher pH Eudragit®L-100-SS dissolves which increases the permeability of the dosage formto correct for reduction in drug solubility, and hence a pH-independentrelease system is achieved¹⁰. A pH-independent controlled release systemwas developed by Howard and Timmins which was composed of sodiumalginate, an anionic polymer, and HPMC¹¹. At low pH sodium alginateprecipitates in the gel layer providing resistance of this layer toerosion. At higher pH values, the alginate forms a soluble salt andhence undergoes erosion. As a result, with increase in pH the releasemechanism changes from predominately diffusion controlled to erosioncontrolled, and the resulting higher permeability of the gel layer makesup for the reduction in the solubility¹¹. A multiparticular devicecoated with walls of controlled porosity was introduced as an approachto delivery of weakly basic compounds. When exposed to water, low levelsof a soluble additive were leached from semi-permeable polymeric coatleading to increased porosity. The sponge like structure forms acontrolled porosity wall, permeable to both water and the dissolveddrug, thereby providing pH-dependent drug release¹².

Existing polymers with pH-dependent solubility, such as methacrylicacid-ethyl acrylate copolymer (Eudragit® L) and hypromellose acetatesuccinate, are typically used as pore former materials for more specificpH-sensitive applications, e.g. protection of acid-labile drugs, delayedrelease, targeted delivery to given regions of the gastrointestinal (GI)tract¹³⁻²³. These polymers are water-insoluble at low pH in the stomachand remain within the coating thus hindering drug release. At higher pHin the small and large intestines, they become water-soluble and leachout from the coating, resulting in a more porous and permeablefilm^(16,24-27). This pH-dependent leaching could reduce the mechanicalstrength of the film and compromise coating integrity, which canincrease the risks of premature drug release and dose dumping in the GItract, leading to unwanted toxicity^(27,28). Furthermore, the filmscould lose the ability to continuously modulate drug permeability oncethe pore former has leached out. Another problem with use ofwater-soluble polymers as pore former is the significantly increasedviscosity of the coating dispersion. High viscosity of the coatingdispersion can cause clogging of equipment parts (i.e. spray nozzle andtubing) and inconsistency in the coating^(29,30).

Alcohol-induced dose dumping (ADD) of modified release (MR) dosage formsis of particular high risk for opiate drugs and drugs with narrowtherapeutic windows. As MR dosage forms contain a large dose, a suddenrelease, known as dose dumping, can happen when alcohol is co-ingestedif the dosage form is not resistant to alcohol. Loss of delayed releaseand prematured drug release than intended can lead to risks of toxicityor side effects. Opiate drugs, when taken in significantly high amounts,can result in side effects, such as severe itching, vomiting, nausea,urinary retention, and respiratory depression³¹. Alcohol resistance ofdosage forms is also important for drugs with narrow therapeutic index,such as theophylline³². Such drugs can produce severe side effects ifdose dumping occurs, and hence should be carefully noted. In 2005, theongoing concern has led the U.S. Food and Drug Administration (FDA) towithdraw Palladone™, a controlled release formulation of hydromorphone,from the market due to increase in fatal risks³³. In addition, alcoholhas shown to prolong or accelerate gastric emptying rate depending onthe alcohol concentration, hence an alcohol resistant andpH-responsiveness technology is necessary³⁴⁻³⁶.

Various approaches have been attempted to reduce ADD. One approach isthe utilization of alcohol insoluble components within the matrix orcore composition. The added component is resistant to alcohol due totheir lack of solubility and ability to alter swellability, thereby,limiting influx of hydroalcoholic media. Another approach is based onthe addition of alcohol-insoluble component to conventional filmcoating, such as ethylcellulose. As the conventional coating is solublein ethanol but insoluble in aqueous media. The added alcohol-insolublecomponent will act to compensate the ethanol solubility of thetraditional film coating^(37,38).

However, matrix system may not be preferred at times compared to coatingsystem. For example, controlled release or, in this particular instance,the alcohol resistance of a matrix or core composition system may dependon several factors involved, including compressibility, hardness,disintegration time, excipient compatibility, etc. In addition, acoating system can achieve zero order release, whereas matrix systemscannot.

One coating technology for preventing ADD is Aquacoat® ARC. Aquacoat®ARC has been developed by blending guar gum (soluble in water, insolublein ethanol) and ethyl cellulose (insoluble in water, soluble in ethanol)as alcohol-resistant film coating³⁹⁻⁴². Aquacoat®ECD30 acts as component1 while guar gum acts as component 2 to compensate the solubility of theother within the hydroalcoholic media. An investigation into theformulation parameters reported that the incorporation of at least 5%guar gum and apparent viscosity of great than 150 cP (of 1% aqueous guargum) is needed to gain alcohol-resistant properties³⁹. A major problemencountered by the use of guar gum is the high viscosity of the coatingsuspension, leading to process challenges. For example, addition of 12%guar gum to Surelease® (ethylcellulose) suspension increased theviscosity drastically, which makes coating process difficult. Uneven andnon-homogeneous coating of dosage form can increase the risk of alcoholdose dumping. Another issue with guar gum is its aqueous solubility. Asguar gum is very soluble in water, the loss of guar gum in aqueous mediais quite significant, which can negatively impact the rate of drugrelease, synonymous to the leaching of water-soluble pore formers.Therefore, a nanoparticulate pore former with little impact on theviscosity of coating suspension and negligible leaching is moreadvantageous.

SUMMARY

A polymeric composite coating for pH-independent controlled release ofweakly basic and acidic drugs has now been developed that functions tomodulate the permeability of the coating continuously and automaticallyin response to the varying pH of the gastrointestinal tract.

In one aspect of the disclosure, a polymeric composite coating isprovided comprising a drug release retardant polymeric matrix andpH-responsive nanoparticulate pore formers that function to modulate thepermeability of the overall composite coating in response to changes inpH throughout the gastrointestinal tract with negligible leaching of thenanoparticulate pore formers.

According to one embodiment, the drug release retardant polymer matrixcomprises any one or a combination of cellulose derivatives, (alkyl)acrylate polymers and derivatives, polyvinyls and copolymers.

In one embodiment, the pH-responsive nanoparticulate pore formercomprises a first polymer grafted to a second polymer, which iscovalently bound to a third polymer.

In one embodiment, the pH-responsive nanoparticulate pore formercomprises of a biocompatible polysaccharide (such as starch) backbonegrafted with a stabilizing emulsifier and a pH-responsive polymeradapted to alter the porosity of the polymeric coating, in which thenanoparticulate pore former is incorporated into, in response to pHchanges in gastrointestinal tract.

According to one embodiment of the disclosure, the first polymercomprises a polysaccharide; the second polymer is a crosslinked polymercomprising of a ionizable polymer; and the third polymer is apolysorbate comprising a (C9-C31)R—C(O)O— group covalently bound to thesecond polymer by a C—C bond between the carbon backbone of the secondpolymer and the R group. According to one embodiment, the ionizablepolymer is any one of polymethacrylic acid, polyacrylic acid, and maleicacid copolymers, and polyvinyl derivatives. According to a furtherembodiment, the ionizable polymer is selected from methacrylicacid-ethacrylate copolymer, poly(2-(dimethylamino)ethyl methacrylate),poly(2-(diisopropylamino)ethyl methacrylate), poly(2-n-morpholinoethylmethacrylate), poly(l-vinylimidazole), poly(2-vinylpyridine), and(4-vinylpyridine).

In a further aspect, a method of achieving pH-independent release of aweakly basic or acidic drug has been provided comprising of applying apolymeric composite coating onto drug-loaded beads, wherein the coatingcomprises a drug release retardant polymer matrixand pH-responsivenanoparticulate pore formers that functions to modulate the permeabilityof the coating in response to low and high gastrointestinal pH in orderto compensate any changes in drug solubility.

In yet another aspect, a method of achieving alcohol-resistant releaseof drugs has been provided, which comprises of application of analcohol-resistant polymeric coating, wherein a nanoparticulate poreformer functions to resist ADD throughout the gastrointestinal tractwith negligible leaching of the nanoparticulate pore former in thepresence of alcohol.

These and other aspects of the present disclosure will become apparentfrom the following detailed description by reference to the figures. Itshould be understood, however, that the detailed description and thespecific examples while indicating preferred embodiments of thedisclosure are given by way of illustration only, since variousmodifications and changes within the spirit and scope of the disclosurewill become apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 graphically illustrates the relative viscosities of 15% w/vSurelease® dispersion without pore formers as control and 15% w/vSurelease® dispersion with either the terpolymer, PVP, Eudragit L, orHPMC (n=3);

FIG. 2 graphically illustrates the tensile strength of wet controlmembrane at 0% pore former level and wet composite membrane at 10% poreformer level that were immersed in pH 6.8 phosphate buffer over 24 hours(n=3);

FIG. 3 graphically illustrates the Young's modulus of wet controlmembrane at 0% pore former level and wet composite membrane at 10% poreformer level that were immersed in pH 6.8 phosphate buffer over 24 hours(n=3);

FIG. 4 shows representative SEM photographs of the cross-sectional areaof the control membrane and the composite membranes at 5%, 10%, and 15%pore former levels of terpolymer;

FIG. 5 shows representative SEM photographs of the surfaces of diltiazemHCl beads coated with the composite membrane at 5%, 10%, and 15% poreformer levels and beads coated with Surelease and HPMC at 15% poreformer level. The inserts are close-ups of the surface at 850×magnification;

FIG. 6 graphically illustrates the glass transition temperature (T_(g))of the control membrane, the composite membranes at 5%, 10%, and 15%pore former levels, and pure terpolymer nanoparticles (n=3);

FIG. 7 graphically illustrates the permeability of verapamil HCl at pH1.2 and pH 6.8 of control membrane and composite membranes at 5% and 10%pore former level (n=3);

FIG. 8 graphically illustrates the permeability of theophylline at pH1.2 and pH 6.8 of control membrane and composite membrane at 10% poreformer level (n=3);

FIG. 9 graphically illustrates the swelling ratios of control membraneand composite membrane at 10% pore former level at pH 1.2 and 6.8 (n=3);

FIG. 10 graphically illustrates fractional release over time of a weaklybasic drug, diltiazem HCl, in 0.1 N HCl and pH 6.8 phosphate buffer fromdrug-loaded beads coated with the composite coating with 5% pore formerlevel of the terpolymer (n=3);

FIG. 11 graphically illustrates fractional release over time of a weaklybasic drug, diltiazem HCl, in 0.1 N HCl and pH 6.8 phosphate buffer fromdrug-loaded beads coated with the composite coating with 10% pore formerlevel of the terpolymer (n=3);

FIG. 12 graphically illustrates fractional release over time of a weaklybasic drug, diltiazem HCl, in 0.1 N HCl and pH 6.8 phosphate buffer fromdrug-loaded beads coated with the composite coating with 15% pore formerlevel of the terpolymer (n=3);

FIG. 13 graphically illustrates fractional release over time of a weaklybasic drug, diltiazem HCl, in 0.1 N HCl and pH 6.8 phosphate buffer fromdrug-loaded beads coated with the composite coating with 15% pore formerlevel of HPMC (n=3);

FIG. 14 graphically illustrates the change in diameter ofPDEAEM-g-starch nanoparticles as a function of pH of the medium (n=3);

FIG. 15 shows representative SEM photograph of the cross-sectional areaof the PDEAEM-g-starch nanoparticle-embedded ethylcellulose compositemembrane;

FIG. 16 shows representative SEM photograph of the PDEAEM-g-starchnanoparticles embedded within the ethylcellulose membrane;

FIG. 17 shows kinetics of theophylline release across PDEAEM-g-starchnanoparticles embedded ethylcellulose membrane (N=3)

FIG. 28 shows kinetics of verapamil HCl release across PDEAEM-g-starchnanoparticles embedded ethylcellulose membrane (N=3)

FIG. 39 shows kinetics of ibuprofen release across PDEAEM-g-starchnanoparticles embedded ethylcellulose membrane (N=3)

FIG. 20 shows kinetics of vitamin B12 release across PDEAEM-g-starchnanoparticles embedded ethylcellulose membrane (N=3)

FIG. 21 graphically illustrates the permeability of diltiazem HCl at pH1.2 and pH 6.8 of Eudragit L membrane and composite membranes (TPN) at10% pore former level (n=3)

FIG. 22 graphically illustrates the weight loss of blank (open circles),10% TPN (grey squares), or 10% Eudragit® L (filled triangles) filmsimmersed in pH 1.2 HCl solution over 24 hours (n=3)

FIG. 23 graphically illustrates the weight loss of blank (open circles),10% TPN (grey squares), or 10% Eudragit® L (filled triangles) filmsimmersed in pH 6.8 phosphate solution over 24 hours (n=3)

FIG. 24 shows representative SEM photographs of blank, 10% TPN, and 10%Eudragit® L films after being immersed in pH 1.2 HCl solution and pH 6.8phosphate buffer solution over time.

FIG. 25 graphically illustrates the permeability of theophylline at 0%and 40% ethanol concentration in 0.1 N HCl solution through blankSurelease membrane and terpolymer membrane at 10% pore former level(n=3)

FIG. 26 graphically illustrates the weight loss of blank, 10% TPN, or12% guar gum films at 0% and 40% ethanol concentration in 0.1 N HClsolution over 4 hours (n=3)

FIG. 27 graphically illustrates the medium uptake of blank membrane, 10%TPN, and 12% guar gum films at 0% and 40% ethanol concentration in 0.1 NHCl solution over 4 hours (n=3)

FIG. 28 shows representative SEM photographs of blank, 10% TPN, and 12%guar gum films after being immersed in 0% and 40% ethanol concentrationin 0.1 N HCl (pH 1.2) solution over 4 hours at 100× and 850× resolution

DETAILED DESCRIPTION OF THE DISCLOSURE

A polymeric composite coating for pH-independent controlled release ofweakly basic and acidic drugs is provided comprising of releaseretardant polymeric coating, wherein pH-responsive nanoparticulate poreformers functions to modulate the permeability of the coating inresponse to low and high gastrointestinal pH in order to compensate anychanges in drug solubility.

The term “drug release retardant polymer” as used herein means anypolymer that retards the release of a drug (or any active ingredients inpharmaceutical formulations, nutraceuticals, animal care products, andconsumer products).

A pH-sensitive polymeric nanoparticulate system is provided composing ofthree polymeric components: an ionizable polymer (for example, PMAA),polysorbate 80 (PS 80) and starch. The terpolymeric system (terpolymer)can be incorporated as a pH-responsive pore former into existingcommercial controlled release polymers such as Surelease®. PMAA, PS80,and starch are all generally regarded as safe by the FDA. Due to itsease of chemical modification and high biocompatibility, starch is usedas the backbone of the terpolymer for which the PMAA and PS80 aregrafted on. PMAA is the pH-sensitive component of the nanoparticles,while PS 80 helps stabilize the nanoparticles. PS80 is also a non-ionicsurfactant used as a solubilizing agent and permeation enhancer inpharmaceutical preparations.

The polymeric composite coating can be applied onto tablets and beadsloaded with weakly basic or acidic drugs with pH-dependent solubility inorder to achieve pH-independent controlled release of these drugs. Theterpolymer nanoparticles incorporated within the composite coatingfunction as pH-responsive pore formers by modulating the coatingporosity in response to low and high gastrointestinal pH in order tocompensate any changes in drug solubility due to changes in pH. Theextremely small size of the terpolymer nanoparticles makes them ideal aspH-responsive pore formers due to the highly increased surface area thatenables fast responsiveness to changes in gastrointestinal pH.

The ability of the terpolymer to modulate permeability in response tovarying pH is due to the ionizable polymer component of the terpolymer,which unionizes at low pH and ionizes at high pH. In an embodiment ofthe present disclosure, the ionizable polymer may be polymethacrylicacid derivatives, acrylic acid derivatives, maleic acid copolymers, orpolyvinyl derivatives. For example, the ionizable polymer may be any oneof poly(methacrylic acid), poly(acrylic acid), methacrylicacid-methacrylate copolymer, methacrylic acid-ethacrylate copolymer,poly(2-(dimethylamino)ethyl methacrylate),poly(2-(diisopropylamino)ethyl methacrylate), poly(2-n-morpholinoethylmethacrylate), poly(1-vinylimidazole), poly(2-vinylpyridine), and(4-vinylpyridine). According to one embodiment, the ionizable polymer isPMAA, i.e., poly(methacrylic acid). The degree of ionization of the PMAAchanges the porosity of the composite coating by either dehydrating thecomposite coating at low pH or hydrating the composite coating at highpH. Hydration of the composite coating increases the motility and freevolume of the polymeric chains as well as induces the formation of waterchannels, where drug diffusivity is much higher than in the polymernetwork.

Broadly stated, the present disclosure relates to a polymeric compositecoating with a pH-responsive pore former component. The polymericcomposite coating is ideal for pharmaceutical formulations that requirepH-independent release of weakly basic or acidic drugs.

Embodiments of the disclosure are described by reference to thefollowing specific examples which are not to be construed as limiting.

Example 1—Synthesis of Terpolymer Nanoparticles

An aqueous based free radical dispersion polymerization process usingpotassium persulfate (KPS)/sodium thiosulfate initiator system (STS) wasused to prepare the PMAA-PS80-g-starch nanoparticles in an one-potsynthesis. The polymerizations were conducted in a 250 mL two-neckedflask immersed in a water bath with nitrogen inlet, a condenser, andmagnetic stirrer. The molar ratio of MAA:N,N′-methylenebisacrylamide(MBA):PS80:starch used as the feed composition for nanoparticlesynthesis was 1.00:0.139:0.0248:0.0212. 4.9 mmol of soluble starch wasfirst dissolved in 180 mL of distilled deionized water (DDIW) at 90° C.for 30 minutes. The solution was then cooled down to 65° C. and purgedwith nitrogen for 30 min to remove any dissolved oxygen. After purgingthe starch solution, 0.45 mmol of KPS and 1.36 mmol of STS dissolved in5 mL of DDIW were added to the flask and stirred for 10 minutes. Next0.69 mmol of SDS dissolved together with 0.57 mmol of PS80 in 10 mL ofDDIW were added. Finally, 23.1 mmol of MAA and 3.2 mmol of MBA dissolvedin 10 mL of DDIW were added to the flask to start the reaction. Thereaction was carried out for 12 hours at 65° C. to ensure completeconversion. Following the synthesis, the product was neutralized with 1N NaOH and ultra-centrifuged (Beckman Coulter, CA, USA) at 35,000 rpmfor 40 minutes and freeze-dried for storage.

Example 2—Preparation of Free Films of Polymeric Composite Coating

Free films of polymeric composite coating were prepared by castingSurelease® ethylcellulose dispersion (grade E-7-19040) mixed with thenanoparticles. Nanoparticles at 10% w/w based on the dry ethylcelluloseweight were dispersed in 10 mL DDIW. The mixture was stirred overnightand dispersed with the Ultrasonic Processor (UP100H, Hielscher, Teltow,Germany) for 15 minutes. Surelease® was then added to the mixture at 15%w/v and stirred for 2 hours. The mixture was then poured onto apolytetrafluoroethylene evaporating plate and degassed under vacuum for30 minutes. After degassing, the evaporating plate was dried at 37° C.for 48 hours. Once dried, the membrane was removed from the evaporatingplate and stored at room temperature. Surelease® membranes with HPMCwere prepared in the same manner.

Example 3—Determination of Viscosity of Polymeric Composite CoatingDispersion

Viscosity of polymeric composite coating dispersion was determined inorder to assess its ease of use during the coating process. 5%, 10%, and15% w/w of terpolymer based on dry ethylcellulose weight in 15% w/vSurelease® dispersions were compared to 15% w/w HPMC, 15% w/w PVP, and15% w/w Eudragit L in 15% w/v Surelease® dispersions and also to 15%Surelease® dispersion without pore formers as control. The relativeviscosities (ηrel) were measured with a capillary viscometer aftercalibration with DDIW.

Example 4—Determination of Mechanical Properties of Polymeric CompositeCoating

Mechanical properties such as tensile strength and Young's modulus ofdry and wet composite membranes were determined by using a universaltesting system Instron 3366 with a 10 kN capacity load cell and across-head of 0.05 mm/s. Dry and wet membrane sample were cut with aASTM D-638 Type V specimen cutting die. Dry and wet samples were thensecured by rubberized turn-screw vise grips and properly aligned beforethe start of the test. Dry membranes at 5% and 10% pore former levels ofterpolymer nanoparticles were stored at 21° C. and 45% RH for 24 hoursprior to testing to equilibrate the specimen to testing conditions. Wetsamples at 10% pore former level were immersed in phosphate buffer at37° C. Specimens were cut and tested after 4, 8, and 24 hours of soakingto evaluate the effect of aqueous medium on mechanical properties of thecomposite membrane over time.

Example 5—Determination of Glass Transition Temperature of PolymericComposite Coating

The glass transition temperatures (T_(g)) of composite membranes at 5%,10%, and 15% pore former levels were determined using differentialscanning calorimetry (TA Instruments 2010 DSC, USA). Approximately 7 mgof sample were sealed in standard aluminum pans and heated from 30° C.to 120° C. at a heating rate of 10° C./min in an atmosphere of nitrogen.

Example 6—Determination of pH-Sensitive Permeability of PolymericComposite Coating

The pH-dependence of the permeability of terpolymer composite membranesat 5% and 10% pore former level was determined using standard 3.4 mLSide-Bi-Side diffusion cells (PermeGear, Hellertown, Pa., USA). Themembranes were pre-swollen in either pH 1.2 HCl solution or pH 6.8phosphate buffer and the thickness of the pre-swollen disks weremeasured using a micrometer. The pre-swollen disks were inserted betweenwell-stirred diffusion cells kept at 37° C. The receptor cell containedeither HCl solution or phosphate buffer, while the donor cell contained1 mg/mL of either verapamil HCl, theophylline, or diltiazem HCldissolved in either pH 1.2 HCl solution or pH 6.8 phosphate buffer. Drugconcentration in the receptor cell were measured using a UV-Visspectrophotometer (8453, Agilent, Waldbronn, Germany).

Example 7—Determination of Swelling Properties of Polymeric CompositeCoating

The change in weight of the membrane samples due to the uptake of waterwere measured over time. Samples were cut from composite membranes of10% pore former level and placed in either pH 1.2 HCl solution or pH 6.8phosphate buffer at 37° C.

Example 8—Drug Layering of Diltiazem HCl onto Microcrystalline CelluloseBeads

The composition of the drug solution is listed in Table 1. The drugsolution was prepared by mixing diltiazem HCl with PVP in DDIW. Druglayering of the microcrystalline cellulose (MCC) beads was performedusing a fluid bed dryer assembled with a bottom spray Wurster apparatus(Pro-C-ept Formate 4M8 Fluid Bed, Zelgate, Belgium) and a nozzle size of0.8 mm. Coating parameters used were: inlet temperature of 50° C.; airspeed of 1.0 m³/min; air nozzle pressure of 0.25 bar; and spray rate of1 g/min.

TABLE 1 Composition of diltiazem HCl drug solution. Materials % w/w Wt(g)/220 g batch Dry wt (g) PVP 2 4.4 4.4 Diltiazem HCl 10 22 22 DDIW 85193.6 N/A

Example 9—Application of Polymeric Composite Coating onto Drug-LayeredBeads

The compositions of the polymeric composite coating dispersions arelisted in Table 2. 5% solutions of terpolymer were prepared by mixingthe pore formers in water for 12 hours. The 5% terpolymer solution wasfurther dispersed with the Ultrasonic Processor (UP100H, Hielscher,Teltow, Germany) for another 30 minutes. the polymeric composite coatingdispersions were prepared by adding the 5% solution of either poreformers to Surelease® ethylcellulose dispersion (grade E-7-19040) untilthe target pore former level (5, 10, or 15% based on dry ethylcelluloseweight) and then adding enough DDIW water to dilute the ethylcellulosecontent to 10%. Coating of drug-layered MCC beads was performed usingthe using a fluid bed dryer assembled with a bottom spray Wursterapparatus (Pro-C-ept Formate 4M8 Fluid Bed, Zelgate, Belgium) and anozzle size of 0.8 mm. Coating parameters used were: inlet temperatureof 30° C.; air speed of 0.35 m³/min; air nozzle pressure of 0.375 bar;and spray rate of 1 g/min. 90 g batches of drug-layered beads werecoated to 20% weight gain. After coating, the finished beads were curedfor 24 hours at 60° C.

TABLE 2 Composition of dispersion of polymeric composite coating.Materials % w/w Wt (g)/~227 g Dry wt (g) Surelease ® 40  90 22.5Terpolymer 0.5/1/1.5 1.125/2.25/3.375 1.125/2.25/3.375 DDIW 60 135 N/A

Example 10—Dissolution Study of Coated Drug Beads

Release of diltiazem HCl from the coated beads was determined using anUSP dissolution apparatus I (VanKel VK7000, Varian Inc., Edison, N.J.,USA) and an UV-Vis spectrophotometer (8453, Agilent, Waldbronn,Germany). 0.5 g of coated beads were placed in baskets and immersed in900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37° C. and rotated at100 rpm.

Example 11—Synthesis of PDEAEM-g-Starch Nanoparticles

Briefly, 4 g of maltodextrin was added to 240 mL of water in around-bottom, two-mouthed flask. The solution was placed in a waterbath, stirred and placed under an N₂ purge until the temperature of themixture had reached no less than 60° C., up to a final temperature of70° C. Upon reaching 60° C., 0.4 g of2,2′-azobiz(2-methylpropioniamidine) dihydrochloride was added, followedby 0.4 g of PVP in 10 mL of water. 4 g of 2-(diethylamine)ethylmethacrylate (DEAEM), and 100 μL of ethylene glycol methacrylate(EGDM) in 10 mL ethanol were then added to the mixture to initiatepolymerization, and the flask was sealed and connected to a watercondenser. The mixture was left at 70° C. for 8 hours in an N₂ blanket,and left to stir overnight. Once polymerization reached completion, thedispersion was dialyzed in filtered water in 12,000-14,000 MWCOSpectra/Por® dialysis tubing for 24 hours. After dialyzing, the mixturewas centrifuged at 45,000 RPM at 3° C. for 30 minutes to obtain apellet. The pellets were then lyophilized and stored for future use.

Example 12—Characterization of PDEAEM-g-Starch Nanoparticles UsingDynamic Light Scattering

Lyophilized nanoparticles were reconstituted in phosphate buffer tocreate a 1 mg/mL solution. Nanoparticle solutions were further dilutedin pH 5.5, 6.0, 6.5 and 7.4 phosphate buffers to test pH-sensitivity.Particle size was determined using a Zeta Potential/Particle SizerNICOMP 380 ZLS (PSS/NICOMP Particle Sizing Systems, Santa Barbara,Calif.). Intensity of the laser was maintained at or below 200 mHzduring measurements.

Example 13—Preparation of PDEAEM-g-Starch Nanoparticle-EmbeddedEthylcellulose Composite Membrane

0.270 g of Ethocel (75 cP) and 0.198 g of dried nanoparticles were addedto 8.50 mL ethanol and stirred until homogenous. 0.059 mL of dibutylsebacate was added to the mixture and left to stir overnight topartition into polymer phase. In the subsequent day, the mixture wascast in a 12 mm-diametre Teflon dish and placed in a desiccator to castovernight at 23° C.

Example 14—Determination of Leaching of Pore Formers from PolymericComposite Coating

Changes in the dried weights of the membrane samples due to pore formerleaching were measured. Dry samples from the blank, 10% TPN, and 10%Eudragit® L films were weighed and then placed in either pH 1.2 HClsolution or pH 6.8 phosphate buffer at 37° C. under constant shaking. Atpredetermined time points, the samples were removed and dried at 50° C.for 24 hours and weighed to get weight loss. The morphologicalstructures of blank, 10% TPN, and 10% Eudragit® L films were examined bySEM in their initial dry state or after immersion in pH 1.2 HCl solutionor pH 6.8 phosphate buffer. Samples were thoroughly dried,freeze-fractured, and gold coated before mounted onto sample holderswith double-sided tapes. The SEM photographs were obtained using aHitachi-3400 microscope at 5 kV.

Example 15—Determination of Alcohol Resistance of Polymeric CompositeCoating

Alcohol resistance of the coating was evaluated by weight loss and drugpermeability tests before and after immersed in ethanol aqueoussolutions. Changes in the dried weights of the membrane samples due topore former leaching were measured. Dry samples from the blank, 10% TPN,and 12% guar gum films were weighed and then placed in either 0% or 40%ethanol concentration 0.1 N HCl at 37° C. under constant shaking. At 4hours, the samples were removed and dried at 50° C. for 24 hours andweighed to get weight loss. The morphological structures of blank, 10%TPN, and 12% guar gum films were examined by SEM in their initial drystate or after immersion in either 0% or 40% ethanol concentration 0.1 NHCl. Samples were thoroughly dried and gold coated before mounted ontosample holders with double-sided tapes. The SEM photographs wereobtained using a Hitachi-3400 microscope at 5 kV. Permeabilities of theblank and composite membranes were determined at in both 0% or 40%ethanol concentration 0.1 N HCl. Theophylline, a neutral drug, was usedas a model drug.

Results

Viscosity of Polymeric Composite Coating Dispersion:

The viscosity of the polymeric composite coating dispersion wasdetermined in order to assess the ease of use during the coatingprocess. Coating dispersions with high viscosity can clog equipmentparts such as the spray nozzle and tubing and can also negatively affectthe uniformity of the coating on individual beads as they cannot evenlyspread on the bead surface. Coating dispersions with HPMC have very highviscosities due to the high solubility of HPMC in water even at lowconcentrations. As shown in FIG. 1, Eudragit L and HPMC at 10% poreformer level increased the viscosity of 15% w/v Surelease dispersion by490% and 5560%, respectively. On the other hand, terpolymernanoparticles and PVP at the same pore former level only increased theviscosity by 75.5% and 5.35%, respectively. As pore former levels of theterpolymer nanoparticles increased from 0% to 15%, the viscosityincreased in an approximately linear fashion. HPMC polymer chains arerelatively straight and uncoiled when dissolved in water which greatlyincreases the viscosity of the solution, whereas the terpolymer chainsare cross-linked to form more compacted nanoparticles that do notheavily impact the viscosity of the solution.

Mechanical Properties of Polymeric Composite Membrane:

The mechanical properties of the composite membranes at 5% and 10% poreformer levels were evaluated, whereas composite membrane at 15% poreformer level and membrane with HPMC could not be tested due to cracksand defects of their free films. Table 3 shows the tensile strength andYoung's modulus of the control and membrane composite membranes, whichwere calculated from the applied load versus extension profile.

TABLE 3 Comparisons of mechanical properties between control membranewith no pore former and composite membranes at 5% and 10% pore formerlevels (n = 3). Membrane Tensile Stress (MPa) Young's Modulus (MPa)Control 4.3 ± 0.3 56.9 ± 0.9 5% terpolymer 3.6 ± 0.3 57.5 ± 3.2 10%terpolymer 3.8 ± 0.5 71.0 ± 4.7

A soft and weak polymer is characterized by low values in tensilestrength, elongation at break, and Young's modulus, while a hard andstrong polymer is characterized by high values in these properties. Apolymer that is both soft and strong is characterized by low Young'smodulus, moderate tensile strength, and high elongation at break. Thetensile strengths of the dry control dry and the composite membranes at5% and 10% pore former levels were very similar. The difference intensile strength between the composite membrane and the control membranewere statistically insignificant. The Young's modulus was found to bestatistically significantly higher for the dry composite membrane at 10%pore former level than that of the dry control and 5% pore former level.This suggested that the dry composite membrane became more elastic thandry control at higher pore former levels. In effect, the terpolymersoftened the ethylcellulose without weakening the overall membrane.

The mechanical properties of polymer coatings in their wet state havetremendous impact on the mechanisms of drug release from polymer-coateddosage forms. For Surelease coating, several mechanisms are possibledepending on the tensile strength and flexibility of the coating,including diffusion through a continuous polymer phase, diffusionthrough aqueous pores, and release driven by osmotic effects⁴³⁻⁴⁷.

Both control and composite membranes at 10% pore former level havesignificantly lower tensile strength in their wet state compared totheir dry state (FIG. 2). The wet composite membrane had drasticallylower tensile strength, by 151%, compared to the wet control membraneafter 4 hours in pH 6.8 phosphate buffer. However, tensile strength ofthe wet composite membrane improved over time and was only 21.3% lowerafter 24 hours. On the other hand, the tensile strength of the wetcontrol membrane did not significantly change over 24 hours. The drasticdecrease in tensile strength of the composite membrane may be due to themuch faster water uptake of the terpolymer nanoparticles in comparisonto the ethylcellulose. The sharp interface between the swollennanoparticles and the relatively dry ethylcellulose bulk may haveintroduced additional internal stress in the membrane, thus weakeningit. As the ethylcellulose swelled over time, the interface became lesspronounce and thereby, relieving some of the internal stress of themembrane and increasing the tensile strength.

Young's modulus of the control membrane and composite membrane at 10%pore former level also significantly decreased in their wet state versustheir dry state (FIG. 3). The increased flexibility of both control andcomposite membranes was likely caused by the plasticizing effect ofwater. Water can increase the motility of polymer chains by disruptinginterchain interactions, especially hydrogen bonding. Young's modulus ofthe wet composite membrane did not significantly change over 24 hours,while slightly increasing for the wet control membrane.

T_(g) of Polymeric Composite Membrane:

Increasing pore former level of terpolymer nanoparticles decreased theT_(g) of the composite membrane (FIG. 6). Although the T_(g) did notsignificantly decrease at 5% and 10% pore former levels, the differencein T_(g) became significant at 15% pore former level, lowering the T_(g)by approximately 6° C. The terpolymer nanoparticles may have a slightplasticizing effect on the Surelease membrane as the nanoparticleslikely disrupted the packing of ethylcellulose chains. The PMAA of theterpolymer nanoparticles may have also disrupted any interchain hydrogenbonding between ethylcellulose chains.

Permeability of Polymeric Composite Membrane:

Permeabilities of the control and composite membranes were determined atpH 1.2 and 6.8 (FIG. 7). Verapamil HCl, a weakly basic drug withpH-dependent solubility, and theophylline, a neutral drug, were used asmodel drugs to compare the permeability at pH 1.2 and 6.8. For thecontrol membrane and composite membrane at 5% pore former level, thepermeability of verapamil HCl at pH 1.2 was significantly higher than atpH 6.8. However, the composite membrane at 10% pore former levelexhibited significantly higher permeability of verapamil HCl at pH 6.8than at pH 1.2 by over 2 folds. The permeability of theophylline showedno difference in permeability between pH 1.2 and 6.8 for the control, asexpected (FIG. 8). On the other hand, for the composite membrane at 10%pore former level, the permeability of theophylline at pH 6.8 was over2.6 fold higher than at pH 1.2. Furthermore, the permeability ofdiltiazem at pH 6.8 was over 40 fold higher than at pH 1.2 (FIG. 21).The result suggested that mechanism of permeation enhancement was likelythrough water flux induced by ionized PMAA chains of the nanoparticles,which caused the overall composite membrane to swell. The increasedwater content of the membrane likely induced formation of aqueous poresin which the drug can easily diffuse through.

Swelling of polymeric composite membrane: To confirm that water fluxwere induced by ionization of PMAA of the terpolymer nanoparticle athigher pH, the swelling kinetics of the composite membrane at 10% poreformer level were studied at pH 1.2 and 6.8. FIG. 9 shows swellingkinetics based on the weight of the membranes. Swelling of the membranesstarted to plateau at approximately 4 hours for the control andcomposite membranes. Control membrane had similar swelling at both pH1.2 and 6.8. However, the composite membrane had significantly higherswelling ratio and swelling rate at pH 6.8 than at pH 1.2. At pH 6.8,the higher water content in the membrane increased the motility and freevolume of the ethylcellulose polymer chain as well as induced theformation of water channels^(48,49), where diffusion coefficient of thedrug is much higher, in the polymer network. While at pH 1.2, the PMAAof the nanoparticles became unionized, leading to decreased water fluxand lower permeability. The composite membrane functioned very similarlyto a pH-responsive hydrogel⁵⁰⁻⁵². The composite membrane is ideal forthe controlled release of weakly basic drug. In the stomach, thesolubility of a weakly basic drug is high, however; in the smallintestine the solubility of the drug would decrease due to the higherpH. To compensate for the low solubility in the small intestine, theincreased permeability of the nanoparticle embedded membrane can achievea steady release throughout the GI tract in a pH-independent manner.

Dissolution of Drug-Loaded Beads with Polymeric Composite Coating:

To further test the ability of the terpolymer nanoparticles to modulatethe permeability of the polymeric composite coating, dissolution testswere conducted at pH 1.2 using 0.1 N HCl and at pH 6.8 using phosphatebuffer. Diltiazem HCl was used as a model weakly basic drug due to itspH-dependent solubility. Even at low pore former level of 5%, thecomposite coating was able to sufficiently increase the coatingpermeability to compensate for the lower drug solubility at pH 6.8 (FIG.10). The degree of permeability enhancement at pH 6.8 was furtherincreased at higher pore former levels of 10% and 15% (FIGS. 11 and 12),which allows the composite coating to remain effective in achievingpH-independent release of drugs with low solubility at basic pH.However, 15% HPMC showed higher drug release at pH 1.2 than at pH 6.8(FIG. 13), indicating a lack of permeability enhancement by HPMCrequired to compensate for the decrease in drug solubility at higher pH.The composite coating is an elegant and effective approach in achievingpH-independent controlled release of weakly basic drugs due to itssimplicity and flexibility of enhancing coating permeability in responseto changes in pH.

pH-Sensitivity of PDEAEM-g-Starch Nanoparticles:

The pH-responsiveness of PDEAEM-g-starch nanoparticles is shown in FIG.14. The nanoparticles shrunk in high pH and swelled in low pH with a44.5-59.5% increase in diameter from pH 7.4 to 5.5.

Morphology of PDEAEM-g-Starch Nanoparticle-Embedded EthylcelluloseComposite Membrane:

As portrayed in SEM phtographs (FIGS. 15-16), PDEAEM-g-starchnanoparticles mixed well with ethylcellulose to form a compositemembrane. The membrane was porous when dried.

Permeability of PDEAEM-g-Starch Nanoparticle-Embedded EthylcelluloseComposite Membrane:

Drug permeation kinetics at pH 7.4 and pH 5 across the compositemembrane are shown in FIGS. 17-20. Drug release rate of non-ionic drugtheophylline showed a strong pH dependence. It can be seen that there isa substantial increase in permeability with pH for theophylline (FIG.17) and verapamil (FIG. 18), as expected from theory. However, releaserate of ibuprofen substantially decreases in permeability (FIG. 19).This could be a result of interactions between the membrane andibuprofen that could have altered the properties and/or integrity of themembrane. Release rate of vitamin B12 exhibited a pH dependence (FIG.20). A larger proportion of drug permeated at pH 7.4 than at pH 5.5 forvitamin B12 compared to theophylline, likely due to the larger molecularsize of vitamin B12.

Leaching of Pore Formers from Polymeric Composite Coating:

The weight loss of blank, polymeric composite (10% TPN), and 10%Eudragit® L films were measured to determine the extent of leaching ofpore formers from films at pH 1.2 (FIG. 22) and 6.8 (FIG. 23). After 24hour-immersion in the pH 1.2 medium, both 10% TPN and 10% Eudragit® Lfilms had very similar weight loss (˜6%) to that of blank films, likelydue to water soluble excipients in the EC dispersion product. Since theacrylic acids in Eudragit® L and TPNs were unionized at pH 1.2, bothpore formers were insoluble and leaching at pH 1.2 was negligible. At pH6.8, both blank and 10% TPN-EC films experienced slight weight loss upto 24 hours similar to the films at pH 1.2; whereas 10% Eudragit® Lfilms lost weight rapidly after 4 hours and reached 61% higher weightloss than blank and 10% TPN films after 24 hours. To examine whether theweight loss was correlated to the porosity and integrity of the films,SEM photographs of the films were acquired after the weight loss study.All three types of films showed negligible morphological change afterimmersing in pH 1.2 medium for up to 24 hours (FIG. 24), which wasconsistent with the weight loss results. After immersed in pH 6.8phosphate buffer up to 24 hours, blank films showed no discernable signsof change in porosity (FIG. 24), similar to the films immersed at pH1.2. The 10% TPN films only showed a few small pores after 8 hours,while 10% Eudragit® L films already showed substantial erosions andlarge pores at 2 hours. These results from the weight loss study and thesubsequent SEM examination of the films clearly demonstrated that TPNswere able to mitigate leaching from EC films at both pH 1.2 and 6.8. Thelarge size (˜240 nm in mean diameter) and insolubility rendered bycrosslinking of TPNs made them difficult to migrate out of the EC films.At 10% pore former level, lower than the percolation threshold (i.e.20-30 wt %)⁵³, no interconnected permeable channels could be formed thatallow the TPNs to diffuse out either. Moreover, the similarity of TPNsand EC in chain structure and hydrophobic domains could have impartedtheir high affinity, further maintaining TPNs within the EC mesh. Incontrast, Eudragit® L, as a soluble polymer at pH 6.8, showedsignificant leaching after 2 hours which would weaken the mechanicalstrength of the films.

Permeabilities of theophylline across the blank and composite membraneswere determined at in both 0% or 40% ethanol concentration 0.1 N HCl(FIG. 25). The permeability of theophylline showed a great differencebetween 0% and 40% ethanol concentration for blank membrane at almost 51folds, as expected as ethylcellulose is soluble in ethanol. On the otherhand, for the composite membrane at 10% pore former level, thepermeability of theophylline at 0% and 40% only increased 2.6 folds. Theresult suggested that the composite membrane is alcohol resistant incomparison to blank membrane. FIGS. 26 and 27 respectively exhibitedmuch less weight loss and medium uptake for the terpolymer-containingcomposite membranes than the blank membranes. SEM images (FIG. 8) showedthat the terpolymer-containing membrane was more intact after immersedin 40% alcohol than the blank membrane and guar gum-containing membrane.

In one aspect of the disclosure, a novel pH-responsive polymericcomposite membrane was successfully synthesized by incorporatingterpolymer nanoparticles into ethylcellulose coating. The new compositecoating was homogenous and exhibited good mechanical properties similarto that of ethylcellulose coating with no pore former. The goodmechanical properties, together with the low impact on viscosity of thecoating dispersion and the pH-responsive permeability, make thecomposite coating a good candidate for controlled release formulationand other pharmaceutical applications. We were also able to demonstratepH-independent release of diltiazem HCl from drug-loaded beads coatedwith composite coating. Additionally, the terpolymer showed very lowsolubility in ethanolic solutions, from which an alcohol-resistantcomposite membrane was successfully synthesized.

Generally speaking, the polymeric composite coating and methods hereinare for controlled release of ingredients in pharmaceuticalformulations, nutraceuticals, animal care products, and consumerproducts. Various embodiments and aspects of the disclosure have beendescribed with reference to details discussed above. The description anddrawings are illustrative of the disclosure and are not to be construedas limiting the disclosure. Numerous specific details have beendescribed to provide a thorough understanding of various embodiments ofthe present disclosure. However, in certain instances, well-known orconventional details are not described in order to provide a concisediscussion of embodiments of the present disclosure.

As used herein, the terms, “comprises” and “comprising” are to beconstrued as being inclusive and open ended, and not exclusive.Specifically, when used in the specification and claims, the terms,“comprises” and “comprising” and variations thereof mean the specifiedfeatures, steps or components are included. These terms are not to beinterpreted to exclude the presence of other features, steps orcomponents.

As used herein, the term “approximately” is meant to cover slightvariations that may exist in the upper and lower limits so as to notexclude embodiments where on average most of the dimensions aresatisfied but where statistically dimensions may exist outside thisregion. It is not the intention to exclude embodiments such as thesefrom the present disclosure.

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1. A polymeric composite coating comprising a drug release retardantpolymer matrix, and a pH-responsive nanoparticulate pore former.
 2. Thepolymeric composite coating of claim 1, wherein the drug releaseretardant polymer matrix comprises any one or a combination of cellulosederivatives, (alkyl) acrylate polymers and derivatives, polyvinyls andcopolymers.
 3. The polymeric composite coating of claim 1, wherein thepH-responsive nanoparticulate pore formers comprise a first polymergrafted to a second polymer, which is covalently bound to a thirdpolymer.
 4. The polymeric composite coating of claim 3, wherein thefirst polymer comprises a polysaccharide; the second polymer is acrosslinked polymer comprising of a ionizable polymer; and the thirdpolymer is a polysorbate comprising a (C9-C31)R—C(O)O— group covalentlybound to the second polymer by a C—C bond between the carbon backbone ofthe second polymer and the R group.
 5. The polymeric composite coatingof claim 4, wherein the ionizable polymer is any one of polymethacrylicacid, polyacrylic acid, and maleic acid copolymers, and polyvinylderivatives.
 6. The polymeric composite coating of claim 4, wherein theionizable polymer is selected from methacrylic acid-ethacrylatecopolymer, poly(2-(dimethylamino)ethyl methacrylate),poly(2-(diisopropylamino)ethyl methacrylate), poly(2-n-morpholinoethylmethacrylate), poly(1-vinylimidazole), poly(2-vinylpyridine), and(4-vinylpyridine).
 7. The polymeric composite coating of claim 2,wherein the pH-responsive nanoparticulate pore formers comprise a firstpolymer grafted to a second polymer, which is covalently bound to athird polymer.
 8. The polymeric composite coating of claim 7, whereinthe first polymer comprises a polysaccharide; the second polymer is acrosslinked polymer comprising of an ionizable polymer grafted to thefirst polymer; and the third polymer is a polysorbate comprising a(C9-C31)R—C(O)O— group covalently bound to the second polymer by a C—Cbond between the carbon backbone of the second polymer and the R group.9. The polymeric composite coating of claim 8, wherein the ionizablepolymer is any one of polymethacrylic acid derivatives, acrylic acidderivatives, maleic acid copolymers, and polyvinyl derivatives.
 10. Thepolymeric composite coating of claim 8, wherein the ionizable polymer isselected from poly(methacrylic acid), poly(acrylic acid), methacrylicacid-methacrylate copolymer, methacrylic acid-ethacrylate copolymer,poly(2-(dimethylamino)ethyl methacrylate),poly(2-(diisopropylamino)ethyl methacrylate), poly(2-n-morpholinoethylmethacrylate), poly(1-vinylimidazole), poly(2-vinylpyridine), and(4-vinylpyridine).
 11. A method of preparing pH independent drug releasesystem wherein the method comprises applying a polymeric compositecoating of claim 1 onto drug-loaded beads.
 12. The method of claim 11,wherein the drug release retardant polymer matrix comprises any one or acombination of cellulose derivatives, (alkyl) acrylate polymers andderivatives, polyvinyls and copolymers.
 13. The method of claim 11,wherein the pH-responsive nanoparticulate pore formers comprise a firstpolymer comprising a polysaccharide; a crosslinked second polymercomprising an ionizable polymer; and a polysorbate comprising a(C9-C31)R—C(O)O— group covalently bound to the second polymer by a C—Cbond between the carbon backbone of the second polymer and the R group.14. The method of claim 11, wherein the pH-responsive nanoparticulatepore formers function to modulate the permeability of the overallcomposite coating in response to changes in pH throughout thegastrointestinal tract.
 15. The method of claim 11, wherein the drug isweakly basic or acidic.
 16. A method of preparing alcohol resistant drugrelease system, said method comprising applying a polymeric compositecoating of claim 1 onto drug-loaded beads.
 17. The method of claim 16,wherein the drug release retardant polymer matrix comprises any one or acombination of cellulose derivatives, (alkyl) acrylate polymers andderivatives, polyvinyls and copolymers.
 18. The method of claim 16,wherein the pH-responsive nanoparticulate pore formers function asalcohol-resistant component to the overall composite coating to resistincreased solubility and permeability in presence of alcohol at 40%ethanol concentration in aqueous media.
 19. The method of claim 16,wherein the pH-responsive nanoparticulate pore formers comprise a firstpolymer comprising a polysaccharide; a crosslinked second polymercomprising an ionizable polymer; and a polysorbate comprising a(C9-C31)R—C(O)O— group covalently bound to the second polymer by a C—Cbond between the carbon backbone of the second polymer and the R group.20. The method of claim 17, wherein the pH-responsive nanoparticulatepore formers comprise a first polymer comprising a polysaccharide; acrosslinked second polymer comprising an ionizable polymer; and apolysorbate comprising a (C9-C31)R—C(O)O— group covalently bound to thesecond polymer by a C—C bond between the carbon backbone of the secondpolymer and the R group.